Neurodegenerative diseases are progressive disorders that cause fatal damage to, or nerve cell death. As principal neurodegenerative diseases, known are Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, peripheral nervous system disorders such as typically diabetic neuropathy, etc. Most of those are related to aging, and, in fact, cases that present the symptoms of those diseases increase with aging. However, middle-aged and even young-aged cases may often present the symptoms of those diseases.
As a result of studies relating to the structure and function of brains, the roles of neurotransmitters and neurotrophins are being gradually clarified, but for the most part the causes of neurodegenerative diseases are still unknown. Only for Parkinson's disease, has the relation between it and a specific neurotransmitter, dopamine has been clarified. L-dopa, which is a precursor of dopamine, is used as a medicine for Parkinson's disease. L-dopa relieves the neuropathic manifestation of Parkinson's disease, and maintains function. However, L-dopa does not suppress the progress of neurodegeneration in cases of Parkinson's disease, and it gradually loses its potency with the progress of the manifestation of the disease, or that is, with the degeneration and death of dopamine-based nerve cells. Alzheimer's disease results in the degeneration and death of many types of nerve cells such as acetylcholine-based nerve cells and monoamine-based nerve cells. For this disease, some cholinesterase inhibitors are commercially available and some others are in the development stage. However, those are still within the range of symptomatic treatment for temporarily relieving the neuropathic manifestation of Alzheimer's disease, like L-dopa for Parkinson's disease.
As has been mentioned above, no medicines have been reported for protecting nerve cells from the toxicity of factors causing cell death thereby to suppress the progress of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
It is said that the cell death in neurodegenerative diseases is caused by the toxicity of factors that are intrinsic to the respective diseases. For Alzheimer's disease, for example, it is believed that the intrinsic β-amyloid in the disease is a factor which causes cell death. β-amyloid is a protein seen in the brains of cases of Alzheimer's disease, constitutes senile lentigines that are characteristic of the disease in neuropathology, and is composed of from 40 to 43 amino acids. It has been clarified that, when β-amyloid is added to the primary culture of hippocampus nerve cells, this kills the cells (see Science, Vol. 245, pp. 417-420, 1989); and it has been reported that the coagulation of β-amyloid is indispensable for the expression of its toxicity (see Neurobiology of Aging, Vol. 13, pp. 587-590, 1992; and Journal of Molecular Biology, Vol. 218, pp. 149-163, 1991). For the toxicity expression mechanism of β-amyloid, the following (1) to (4) may be taken into consideration: (1) β-amyloid forms ion channels, through which calcium ions run into nerve cells. (2) β-amyloid promotes the generation of free radicals.
(3) β-amyloid activates tau-protein kinase I (TPK-I) whereby phosphorylation of tau is promoted. (4)β-amyloid activates microglia, which thereby secretes neurotoxin. However, no one has as yet confirmed this.
Recently, it has been clarified that neurotrophins such as IGF-1 (insulin-like growth factor) and NGF (nerve growth factor) inhibit the apoptosis of nerve cells by β-amyloid or the like, and that, for its mechanism, the apoptosis inhibition is related to the inhibition of TPK-I/GSK-3β (glycogen synthase kinase 3) through activation of PI-3 kinase (see J. Neurosci., Vol. 11, pp. 2552-2563, 1991; Science, Vol. 267, pp. 2003-2006, 1995; and J. Biol. Chem., Vol. 272, pp. 154-161, 1997). When PI-3 kinase is inhibited by β-amyloid and TPK-I/GSK-3β is activated, then pyruvate dehydrogenase (PDH) is inhibited, while having an influence on the synthesis of acetylcholine, to thereby lower the acetylcholine content. This is supported by the decrease in the acetylcholine content of the brains of cases of Alzheimer's disease. On the contrary, when PI-3 kinase is activated, then it is expected that not only the nerve cell death is prevented but also the intracerebral acetylcholine content is increased to improve the nervous system condition. In addition, it is also expected that the inhibition of TPK-I/GSK-3β results in the increase in the intracerebral glucose utilization which is lowered in cases of Alzheimer's disease (see J. Biol. Chem., Vol. 269, pp. 3568-3573, 1994; and Endocrinology, Vol. 125, pp. 314-320, 1989). Accordingly, low-molecular compounds having good permeability to the brain and having neurotrophic action may inhibit nerve cell death in cases of neurodegenerative diseases such as Alzheimer's disease, while improving the nervous system condition in those cases.
Known are the following dihydrobenzofuran compounds which are effective for neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, etc.).
1) A compound of the formula: wherein R is a lower alkyl, R0 is hydrogen or an acyl; R1 and R2 are the same or different and are a lower alkyl which may be substituted, or R1 and R2, taken together, are a butadienylene which may be substituted; R3 and R4 each is hydrogen or an alkyl which may be substituted, or R3 and R4, taken together, are a polymethylene; R5 is a lower alkyl, an aromatic group or heterocyclic group which may be substituted (EP-A-273647, JP-A-1-272578).
2) A compound of the formula: wherein R1 and R2 are the same or different and are a hydrogen atom, an acyl, an alkoxycarbonyl, an optionally substituted aliphatic group or an optionally substituted aromatic group; R3, R4 and R5 are the same or different and are an optionally acylated hydroxy, an optionally substituted amino, an optionally substituted alkoxy or an optionally substituted aliphatic group, or two of R3, R4 and R5 may be linked together to form an optionally substituted carbocyclic group: R6 and R7 are the same or different and are an optionally substituted aliphatic group, provided that at least one of R6 and R7 has methylene at α-position; and R8 and R9 are the same or different and are a hydrogen atom, an optionally substituted aliphatic group or an optionally substituted aromatic group, or a salt thereof (EP-A-483772, JP-A-5-140142).
Also known are the following benzofuran compounds and dihydrobenzofuran compounds.
3) A compound of the formula: wherein A is —O—, —S(O)m—, —N(R11)—, —CH2CH2-, or —CH═CH—; m is 0, 1, or 2; X is a bond or C1-4, alkylidenyl: R2 is a group of the formula: —NR4R5 wherein R4 and R5 are independently C1-6 alkyl, etc.); R is hydroxy, halo, C3-8 cycloalkyl, C2-7 alkanoyloxy, C1-6 alkoxy, phenyl, etc.; R1 is hydroxy, halo, hydrogen, C3-8 cycloalkyl, C2-7, alkanoyloxy, C1-6 alkoxy, phenyl, etc., or a pharmaceutically acceptable salt, which is useful for the prevention and treatment of physiological disorder associated with an β-amyloid such as Alzheimer's disease and Down's syndrome (WO 95/17095).
4) A compound of the formula: wherein R1 is hydrogen or a lower alkyl; R2 is a methyl substituted by carboxy, alkoxycarbonyl, cyano, halogen, aryl or heterocyclic group, or C2-15 chain-like hydrocarbon residue having no lower alkyl at α-position which may be substituted by carboxy, alkoxycarbonyl, cyano, halogen, aryl or a heterocyclic group; R3 is a lower alkyl: R4 is hydrogen of an acyl; R5 and R6 each is a lower alkyl of a lower alkoxy, or R5 and R6, taken together, are butadienylene, or a salt thereof, which has 5- or 12-lipoxygenase inhibiting actions (EP-A-345593, JP-A-2-76869).
5) A compound of the formula: wherein R1 is hydrogen or a lower alkyl; n is 1 to 6; X is sulfur which may be oxidized, oxygen or imino which may be substituted; R2 is methyl or an organic residue bonded through methylene, methylene or quaternary carbon; R3 is a lower alkyl; R4 is hydrogen or an acyl; R5 and R6 each is a lower alkoxy or a lower alkyl, or R5 and R6, taken together, are butadienylene, or a salt thereof, which has a 5-lipoxygenase inhibiting action (EP-A-345592, JP-A-2-76870).
6) A compound of the formula: wherein R is hydrogen or methyl; R1 and R2 each are methyl or ethyl, or R1 and R2 taken together are a saturated heterocyclic group; and X is bromo, chloro, fluoro or hydrogen, or a pharmaceutically acceptable salt thereof, which is useful for inhibiting bone loss (EP-A-722726).
Known are the following indole compounds.
7) A compound of the formula: wherein R1 is —X(CH2)nAr, —X(CH2)nR8 etc., R2 is hydrogen or Ar etc., P1 is —X(CH2)nR8, P2 is —X(CH2)nR8 etc., R3 is hydrogen, R11, OH, C1-8 alkoxy, S(O)q R11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, —R11CO2R7, —XR9—Y, XY or —X(CH2)nR8, wherein methylene of the —X(CH2)nR8 may be unsubstituted or substituted by one more —(CH2)nAr, R8 is hydrogen, R11 etc., R9 is C1-10 alkyl, C2-10 alkenyl, phenyl, etc., R11 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, etc., X is (CH2)n, O, S(O)q, Y is CH, or —X(CH2)nAr, Ar is phenyl, naphthyl, etc., q is 0, 1 or 2, n is an integer of 0 to 6, or a pharmaceutically acceptable salt thereof, which is useful for antagonizing endothelin receptors and treating cerebrovascular diseases (WO 94/14434, JP-A-8-504826).
8) A compound of the formula: wherein one of R and R0 is and the other is C1-6 alkyl, C1-6 cycloalkyl or phenyl-(CH2)m-wherein R4, R5 and R5a are hydrogen, etc.; m is 1, 2 or 3; R2 is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, phenoxy, benzyloxy, etc.; R3 is hydrogen, C1-3 alkyl, C1-3 alkoxy, phenoxy, benzyloxy, etc.; X is —(CH2)n— or —CH═CH—; n is 0, 1, 2 or 3; R6 is hydrogen or C1-3 alkyl, or a salt thereof, which has cholesterol biosynthesis inhibiting activity (WO 84/02131).